Production of polymorphic forms I and II of finasteride by complexation with group I or II metal salts

ABSTRACT

Polymorphic Form (I) finasteride is prepared by first forming a substantially insoluble complex of finasteride and a Group (I) or Group (II) metal salt, such as lithium bromide, and then dissociating the complex by dissolving away the salt component with water, so as to obtain substantially pure Form (I) polymorphic crystalline finasteride.

This application a 371 of PCT/CA99/01017 filed Nov. 1, 1999, now WO01/32683

This invention relates to finasteride, a 4-aza-steroid compound whichexhibits pharmaceutical activity as an inhibitor of the enzymetestosterone 5-α-reductase, and is useful in the treatment of prostatecancer. More specifically, it relates to processes for preparingfinasteride in a specific, polymorphic form.

BACKGROUND OF THE INVENTION

Finasteride is, chemically, (5α,17β)-N-(1,1-dimethylethyl)-3-oxo-4-aza-androst-1-ene-17-carboxamide, ofchemical structural formula:

It is reported to be active in inhibiting the activity of the enzymetestosterone-5-α-reductase, which causes reduction of testosterone inthe body to dihydrotestosterone, DHT, implicated in the enlargement ofthe prostate and consequent development of malignant conditions namelyprostate cancer. Accordingly, finasteride is prescribed for alleviationof prostate cancer.

Finasteride can exist in two different polymorphic forms, Form I andForm II, which differ from one another in respect of their crystallinestructure. The different polymorphic forms can be prepared by control ofthe crystallization conditions. Finasteride polymorphic Form I is theusual form and is the form which is marketed as the active ingredient ofthe finasteride drug formulation PROSCAR®. According to Canadian PatentApplication 2,103,107 Dolling et al. (equivalent to European patentapplication 0599376), finasteride polymorphic Form I is characterized byan X-ray powder diffraction pattern having d-spacings of 6.44, 5.69,5.36, 4.89, 4.55,4.31, 3.85, 3.59 and 3.14. According to the sameCanadian patent, finasteride polymorphic Form II is characterized by anX-ray powder diffraction pattern having d-spacings of 14.09, 10.36,7.92, 7.18, 6.40, 5.93, 5.66, 5.31, 4.68, 3.90, 3.60 and 3.25.

The preparation of finasteride is described and claimed in U.S. Pat. No.4,377,584 and further described in U.S. Pat. No. 4,760,071. Otherpatents which pertain to the preparation of finasteride include CanadianPatent application 2,029,859; U.S. Pat. Nos. 5,084,574 and 5,116,983 andCanadian patent applications 2,049,882 and 2,049,881. All these teachthe conversion of a final intermediate to finasteride, which is purifiedand isolated as a crystalline solid. Although finasteride polymorphs arenot mentioned specifically in these items of prior art, the finasterideobtained using them, as a crystalline solid, must be in one or other ofthe known polymorphic forms, or a mixture of both of them.

Aforementioned Canadian Patent Application 2,103,107 Dolling et al.,published May 20, 1994, describes preparations of finasteride and thespecific polymorphic Form I and Form II thereof. In particular, itteaches that polymorphic Form I can be prepared by crystallization froma mixture of finasteride in an organic solvent and optionally water,such that the amount of organic solvent and water in the mixture issufficient to cause the solubility of the non-solvated form offinasteride (Form I) to be exceeded and the non-solvated form offinasteride to be less soluble than any other form of finasteride in themixture. It also teaches that the polymorphic Form I of finasteride canbe prepared by heating the polymorphic Form II of finasteride to atleast 25° C. in water or an organic solvent for a sufficient period oftime to effect the conversion. The same reference teaches thatpolymorphic Form II finasteride can be prepared by crystallization froma mixture of finasteride in an organic solvent and water, such that theamount of organic solvent and water in the mixture is sufficient tocause the solubility of the solvated form of finasteride to be exceededand the solvated form of finasteride to be less soluble than any otherform of finasteride in the mixture, followed by recovery of the solidand removal of the solvent therefrom; or by heating polymorphic Form Ifinasteride to at least to about 150° C. for sufficient time to completethe conversion.

Purifying crude organic compounds by treating with Group I and Group IImetal salt in a non-hydroxylic solvent to precipitate metal saltcomplexes has been described in GB 2094795, U.S. Pat. No. 4,452,994 andU.S. Pat. No. 4,529,811. The hypothesis has been offered that thecrystal lattice energy between the very small ion radius of the Group Ior Group II metal cation and the much larger ion radius of the chosenanion tends to promote the inclusion of organic substances in thelattice when such substances are capable of helping the solvation of thesmall cation; but, the actual formation of such complexes cannot bereliably predicted for complex molecules and so must be demonstrated byexperiment.

DESCRIPTION OF THE INVENTION

It is an object of the present invention to provide a novel process forpreparing finasteride in its pharmaceutically desirable, polymorphicForm I.

It is a further object of the invention to provide novel intermediatesuseful in preparation of polymorphic Form I finasteride and in otheraspects of finasteride preparation.

According to one aspect of the present invention, there is provided aprocess of preparing polymorphic Form I finasteride, which comprisespreparing a finasteride—Group I or Group II metal salt complex, in thepresence of a non-hydroxylic solvent, dissociating the complex byaddition of acidified water thereto, and recovering the crystalline FormI finasteride so formed.

According to a second aspect of the present invention, there areprovided chemical complexes of finasteride and the salt of a Group I orGroup II metal, said complexes being dissociable upon addition ofacidified water thereto, to yield water-insoluble polymorphic Form Ifinasteride.

According to a further aspect of the invention, there is provided aprocess for preparing chemical complexes of finasteride and a Group I orGroup II metal salt, which comprises dissolving crude finasteride in anon-hydroxylic, chemically inert, organic solvent, and adding to thesolution so formed a salt of a Group I or Group II metal.

The finasteride-metal salt complexes formed in the process of thepresent invention have been found, by X-ray powder diffraction, to benearly amorphous solids. Neither the spectral lines of Form I or Form IIof finasteride are present in these amorphous solids. When thesecomplexes are dissociated according to the process of the invention, byaddition of acidified water thereto, the metal salt is dissolved and thesolid which is obtained upon filtration, surprisingly and unpredictably,turns out to be finasteride Form I. The precursor complexes, and anyfinasteride solvates initially present, as impure substances, do not ofcourse exhibit polymorphic crystalline forms.

Another aspect of the invention is a method of isolating finasteride insubstantially pure, polymorphic Form I, from a solution thereof in anorganic non-hydroxylic solvent, which comprises adding to said solutiona salt of a Group I or Group II metal to form a sparingly solublecomplex thereof with finasteride, separating the finasteride complex byfiltration, and adding acidified water thereto to break the complex andform substantially pure, isolatable polymorphic Form I finasteride.

Addition of acidified water e.g. water containing about 10% v/v aceticacid, to the amorphous solid complex removes the metal salt bydissolution into the aqueous solution, and catalyses the transformationof the finasteride component, which never dissolves, into polymorphicForm I finasteride in substantially pure condition, which can befiltered, washed and dried.

The Group I or Group II metal salts preferably used In the presentinvention are lithium salts and calcium salts, and most preferablylithium salts with relatively large anions, for example bromide, iodide,tetrafluoroborate, perchlorate, hexafluorophosphate and the like.Especially preferred is lithium bromide.

In the preparation of the finasteride-metal complexes according to theinvention, finasteride in any of its polymorphic forms, as mixtures ofpolymorphic forms, or as a solvate with an organic solvent, or in impureform, in solution in a non-hydroxylic, nonreactive organic solvent, isdissolved in a non-hydroxylic organic solvent which does not containcomplexable functional groups which will interact with the finasteride.In a particular preferred embodiment, the finasteride solution is thatresulting from the work-up of the reaction mixture from the chemicalsynthesis of finasteride, for example by the method of reacting (5α,17β)-N-(1,1-dimethylethyl)-3-oxo-4-aza-androstan-17-carboxamide withdichlorodicyanoquinone and bistrimethylsilyltrifluoroacetamide insolution in an non-hydroxylic inert organic solvent. The metal salt isadded to this solution, and sparingly soluble finasteride-metal saltcomplex precipitates. This finasteride-metal salt complex can optionallybe dried, with or without the application of heat Suitable solventsinclude hexanes and other aliphatic and cycloaliphatic hydrocarbons,aromatic hydrocarbons such as benzene, toluene, xylenes, halogenatedaliphatic hydrocarbons such as methylene chloride and other chlorinatedhydrocarbons, ethers such as diethylether, diisopropyl ether andt-butylmethyl ether, and ketones such as methyl isobutyl ketone, andmixtures of two or more mutually compatible such solvents. The quantityof solvent is not critical.

The finasteride-metal salt complexes may be prepared at any suitabletemperature at which the chosen solvent remains liquid. The chosentemperature is not critical. Room temperatures are suitable andconvenient. Similarly the stoichiometry of the finasteride and the metalsalt is not critical, although operating at dose to stoichiometricratios is economical and avoids waste of reagents.

The complex formation benefits from the presence in the organic solventsolution of a small, catalytic quantity of water or lower (C₁-C₆)alkanol. This has the effect of increasing the rate of formation of thecomplex. The catalyst quantity should be chosen so as to be adequate toexert its catalytic, accelerating effect, but not sufficient to competesignificantly for the metal salt or to increase significantly the lowsolubility of the complex. Amounts up to about 1% of Water or loweralkanol are suitable.

BRIEF DESCRIPTION OF THE DRAWING

The attached FIGURE shows three X-ray powder defraction patterns.

EXAMPLES

The invention is illustrated in the following specific examples.

Example 1 Preparation of Finasteride-lithium Bromide Complex

Into a 100 ml r.b. flask equipped with a magnetic stirrer and a nitrogeninert atmosphere was weighted 3.71 gm of finasteride. Methylene chloride(20 ml) was added and the slurry astirred to dissolve the substrate. Tothe clear light yellow solution was added 0.87 g of anhydrous lithiumbromide. The solid was washed down into the reaction with 5 ml ofmethylene chloride. The slurry was stirred. Within one minute add 1 dropof n-propanol from a disposable pipette. The slurry was stirredovernight with exclusion of moisture under an inert nitrogen atmosphere.The slurry is filtered on a Buchner funnel and the flask and solidwashed with 10 ml of methylene chloride. After drying the solid at 50°C. in vacuum the solid complex weighs 4.17 g. The methylene chloridesolution contains 0.35 g of nonvolatile residue.

Example 2 Preparation of Finasteride Form I

In a 25 ml r.b. flask equipped with a magnetic stirrer and a staticnitrogen purge was placed 0.53 g of finasteride-lithium bromide complex.To this was added 10 ml of 9:1 v/v water/acetic acid and the slurry wasstirred for two hours at 50° C. The slurry was cooled to 20-25° C. andfiltered. The solid on the filter was washed with water and dried invacuum at 40-45° C. The solid weighed 0.37 g.

Three different samples of finasteride prepared in three separateexperiments according to this Example 2 where analyzed by x-ray powderdiffraction, and the single FIGURE of accompanying drawings shows thesethree x-ray powder diffraction patterns. They are identical to oneanother, and identify the products as finasteride Form I. Furtherconfirmation of the identity of the product as finasteride Form I wasobtained by differential scanning calorimetry.

I claim:
 1. A process of preparing polymorphic Form I finasteride, whichcomprises preparing a finasteride—lithium or calcium salt complex, inthe presence of a non-hydroxylic solvent, dissociating the complex byaddition of acidified water thereto, and recovering the crystalline FormI finasteride as formed.
 2. The process of claim 1 wherein the metalsalt of the complex is a lithium salt with a relatively large anion. 3.The process of claim 2 wherein the lithium salt is lithium bromide. 4.The process of claim 1, wherein the acidified water is a water-aceticacid mixture.
 5. The process of claim 1 wherein the non-hydroxylicsolvent is an aliphatic hydrocarbon, a cycloaliphatic hydrocarbon, ahalogenated aliphatic hydrocarbon, an aromatic hydrocarbon, an ether, aketone or a mixture of two or more compatible such solvents.
 6. Theprocess of claim 5 wherein the solvent is methylene chloride.
 7. Achemical complex of finasteride and lithium or calcium metal salt, saidcomplex being dissociable upon addition of acidified water thereto, toyield water-insoluble polymorphic Form I finasteride.
 8. The complex ofclaim 7 wherein the metal salt is a lithium salt with a relatively largeanion.
 9. The complex of claim 8 wherein the metal salt is lithiumbromide.
 10. A process for preparing a chemical complex of finasterideand a lithium or calcium metal salt, which comprises dissolving crudefinasteride in a non-hydroxylic, chemically inert, organic solvent, andadding to the solution so formed a salt of a lithium or calcium metal.11. The process of claim 10 wherein the salt is a lithium salt with arelatively large anion.
 12. The process of claim 11 wherein the salt islithium bromide.
 13. The process of claim 10, catalysed by a catalyticamount of water or lower (C₁-C₆) alkanol in the reaction medium.
 14. Amethod of isolating finasteride in substantially pure, polymorphic FormI, from a solution thereof in an organic non-hydroxylic solvent, whichcomprises adding to said solution a salt of a lithium or calcium metalto form a sparingly soluble complex thereof with finasteride, separatingthe finasteride complex by filtration, and adding acidified waterthereto to break the complex and form substantially pure, isolatablepolymophic Form I finasteride.
 15. The method of claim 14 wherein thesalt is a lithium salt with a relatively large anion.
 16. The method ofclaim 15 wherein the salt is lithium bromide.
 17. The method of claim14, wherein the insoluble complex is formed in the presence of acatalytic amount of water or lower (C₁-C₆) alkanol.